Tuberculosis (TB) is an important disease globally and remains a threat to the United States. In some parts of South Africa 1% of the population develops TB disease annually, partly because of the very high rates of HIV infection in that country, an infection that makes people susceptible to secondary infection by TB. The way in which the body resists TB via the immune response is only partly understood, which creates difficulty in understanding what properties a new vaccine against the TB should have. Furthermore the body's own immune response inadvertently can make TB worse by reacting strongly to parts of the bacterium responsible. We are therefore propose a collaboration between a leading basic Science group at the National Institutes of Health (NIH) and a group of researchers in South Africa who care for many TB patients. The aim is to investigate in humans recent findings in the mouse model that have the potential to improve our understanding and thus prevent and treat TB. We will assemble groups of TB patients from whom samples of blood and from the disease site will be made available. We will also track the progress of the patients during TB antibiotic treatment. We will use the materials from the patients to test several ideas that have arisen from NIH. The first is that a specific type of protective blood cell (called a CD4 T lymphocyte), depleted by HIV infection, is most effective at leaving the blood and entering tissues where TB infection is present. Should this prove the case it would be logical to try to induce such cells when designing vaccines against TB. The second idea is that the balance of protective and tissue-damaging immunity is strongly influenced by inflammatory mediators called eicosanoids, and that the best balance is required to hold TB at bay, rather than contribute to tissue damage. In turn, the production of eicosanoids is regulated by an immune response signalling molecule called Interleukin-1 whose importance and cell source may have been overlooked in tuberculosis. The third idea is that the balance of the human molecules hemoxygenase-1 and matrix metalloproteinase 1 may also influence the pattern of inflammation seen in TB and thus the treatment outcome. Hemoxygenase-1 ordinarily breaks down the haemoglobin molecule that contributes red pigment to blood but is also involved in a number of stress responses, including to infection. Matrix metalloproteinase 1 breaks down collagen and is normally involved in wound repair, but it is increased in TB and thus could be abnormally involved in the tissue damage, which in turn makes it more difficult for antibiotics to penetrate lesions due to TB. Via this work, this project will improve understanding of the immune response to TB, enhancing our ability to tackle this devastating condition.